Current treatments for alcohol abuse and dependency are marginally effective. Application of naltrexone, an opiate antagonist, appears to have only a moderate effect in reducing drinking and is not sufficiently effective in treating some sub-populations of problematic alcohol consumers or in preventing relapses. Recent attempts of using multiple drug combinations, where each individual drug addresses a different target set or neurotransmitter system, appear to improve efficacy in curtailing alcohol consumption. Concerns of multiple drug combination regimens, however, are the combined drug side effects, toxicology and pharmacokinetic issues, adding to the stress on the already stressed liver. Developing and evaluating new and more potent medications for alcoholism is still a high priority. Single agents that address multiple CNS targets may be especially attractive. The proposed Phase I research is focused on finding novel small organic molecules with modulating activities at specific membrane receptors in multiple CNS target classes. The successful execution of the proposed research will produce a suite of novel molecules that selectively modulate activity at different opiate receptor subtypes and concurrently at a specific serotonergic receptor subtype. The compounds may be used as research tools to aid in the understanding alcohol addiction and abuse, and later become the basis for therapeutics to treat alcoholism. The success of our approach will rely on the innovative integration of in silico and in vitro screening methods and large readily accessible chemical libraries. The ensuing Phase II research will focus on improving the pharmacological properties of the active compounds in order to enhance the potential for finding new and safe medications for treating alcoholism.